We propose to study the effects of dietary vitamin E on the prevention and treatment of a progressive disease of the kidney, IgA nephropathy, the most common primary glomerulonephropathy, which accounts for nearly 30% of end-stage renal disease throughout the world. In a study on an IgA rat model, we obtained experimental data implicating excessive production of oxygen free radicals in the pathogenesis of this disorder. We demonstrated that dietary supplementation with vitamin E in this model, attenuated hematuria and proteinuria, stabilized renal blood flow and reduced lipid peroxidation of the renal parenchyma. These findings suggest that increased vitamin E intake could modulate progressive renal injury in this disease state. Therefore, we propose to study whether supplementation with vitamin E lessens renal injury in children with IgA nephropathy. Such children are the ideal subjects to test the effects of early treatment on this slowly progressive disease. We also aim to study the mechanisms of vitamin E "modulation of cell integrity and repair" by using molecular biological techniques in an animal model of IgA nephropathy. The first set of experiments will test the hypothesis that oral administration of vitamin E protects against renal damage. Supplemental vitamin E will be given for 2 years to children with IgA nephropathy in a double-blind, placebo-controlled experimental design. The primary end point will be the incidence of hematuria; secondary end points will be changes in microalbuminuria, glomerular filtration rate and renal blood flow. Compliance will be monitored by plasma vitamin E concentrations. The second set of experiments will study the mechanisms of action of vitamin E in modulating renal injury and repair in the animal model of IgA nephropathy. We will identify the critical cytokines and map out the sequence of events which stimulates mesangial cell proliferation and increases autocrine release of platelet-derived growth factor and transforming growth factor-Beta. Increased expression of these growth factors in turn promotes synthesis of extracellular matrix proteins culminating in glomerulosclerosis. We will determine how vitamin E interrupts this pathogenetic sequence of events and prevents progression of experimental IgA nephropathy. These clinical studies and animal experiments offer unique opportunities to examine the role of this dietary supplement in the prevention and treatment of a prevalent kidney disease and how this nutrient modulates renal repair mechanisms.